The primary objective is to establish an alternative method of reducing opioids. Dose-extending placebos could reduce overall opioid intake, decreasing physiological dependence, and still provide effective pain management, thus preventing pain interference with daily functioning. Participants will be enrolled from the R. Adams Cowley Shock Trauma Center (STC) in Baltimore Maryland. They will be randomised to three arms: Arm 1 will be a full dose (FD) group, which will receive oxycodone (5 mg) and non-steroidal anti-inflammatory drugs (NSAIDs) dosed in accordance with the shock trauma guidelines for acute pain in Orthopaedic Injury. Arm 2 will be a partial reduction (PR) group, which will receive oxycodone (5 mg), NSAIDs, and dose-extending placebos to reach a 50% reduction of the total intake of opioids. Finally, Arm 3 will be a control (C) group receiving NSAIDs and placebos. The local STC therapeutic protocol for pain management for NSAIDs includes ketorolac tromethamine intravenous (15 or 30 mg every 8 hours), adjusted with ibuprofen, meloxicam and celecoxib based on patients’ effectiveness and side effects profiles. Secondary objectives are to assess the acceptability and feasibility of recruiting participants with traumatic injuries to successfully participate in the trial, including the 2-week, 1-month, 3-month and 6-month follow-ups for pain and opioid use, are investigated. This PoC study will inform and determine appropriate power for a future larger randomised controlled trial.

H1: We hypothesise that participants in the PR arm will experience a clinically meaningful improvement in pain management as compared with the FD arm, as detailed in figure 1.

H2: We hypothesise that participants in the PR arm will experience significantly better outcomes than participants in the C arm.

H3: We hypothesise feasibility and acceptability of this method of reducing opioids on adequate training of the clinical staff and family members.

We plan to conduct a double-blinded, randomised controlled PoC study to examine the learning mechanisms and efficacy of dose-extending placebos in participants with any traumatic injury requiring opioid medications for pain management. We will recruit and randomise 159 participants with traumatic injuries to one of three study arms according to a 1:1:1 schedule of randomisation: arm 1/FD group will receive oxycodone (5 mg) and NSAIDs and will be dosed in accordance with the STC therapeutic protocol for pain management guidelines for NSAIDs. Arm 2/PR group will receive oxycodone (5 mg), NSAIDs and placebos to reach a 50% reduction of the total intake of opioids. Finally, arm 3/control (C) group will receive NSAIDs and placebos. The study schema is presented in figure 2.

The study will be conducted at the STC, a free-standing dedicated trauma hospital and provides the highest level of care for critically ill and injured participants in the state as the primary adult resource centre for Maryland’s emergency medical services system. The STC is the specialty referral centre for the State of Maryland for neurotrauma and orthopaedic surgery. This study will start recruiting in January 2020.

A total of 159 participants will be enrolled into this study. Participants will be identified by the study investigators’ routine review of patients who have been admitted to the STC with a traumatic injury requiring opioid medication for pain management. The study investigator or research team delegate will approach potentially eligible patients to confirm interest in the study. If the patient is interested, the research team will discuss the study details as outlined in the Institutional Review Board (IRB)-approved informed consent form (ICF). Patients will be given ample time to read the ICF and ask questions. If the patient agrees to participate in the relieving acute pain trial, the patient and the research team member who conducted the informed consent discussion will sign and date the ICF and Health Insurance Portability and Accountability Act (HIPAA) authorisation form. The informed consent process is documented on a checklist which includes confirmation that the participant freely agrees to participate and comprehends the study purpose, procedures and expectations. The research team will proceed with confirmation of patient eligibility via chart review. Moreover, a plan by the primary service to adhere to the shock trauma protocol for NSAID use is a requirement for enrolment. Participants are free to withdraw their participation at any point in the study with or without reporting a reason. Withdrawal of participation in the study is also documented on a participation withdrawal form.

Broad eligibility is proposed to increase the generalizability and feasibility of the trial. There are no exclusions based on sex, race or ethnicity in this trial.

Participant randomisation will only occur once written informed consent is obtained and eligibility is confirmed by investigators. The study team will inform Investigational Drug Services (IDS) Pharmacy at the University of Maryland Medical Center of all newly enrolled participants in the study. IDS will then randomise participants according to the randomisation table generated by IDS pharmacy into one of the three treatment groups: NSAIDs with 5 mg oxycodone (FD arm), NSAIDs with oxycodone and placebos (PR arm) or NSAIDs with placebo (C arm), according to a 1:1:1 schedule of randomisation. IDS pharmacy will be responsible for medication dispensing and delivery to the floor during the trial. The participant will start to receive the study drug within 24 hours of the normally planned opioid administration, ideally as the participant’s first opioid medication while hospitalised. All staff involved with the protocol are fully trained on the procedures and are given emergency contacts of the study team in case of incident.

Participants, investigators, care providers, data collectors and other research team members will not be aware of group allocation. The IDS pharmacy staff, who will prepare the blinded medications for each participant, will be unblind to the treatment assignment.

Oxycodone and placebo oral suspensions are manufactured by IDS Pharmacy at the University of Maryland Medical Center. All study medications are prepared as suspensions to accommodate administration with a potentially broad range of participants (eg, intubated participant). Oxycodone and placebo suspensions are identical in terms of appearance, taste and smell; both suspensions appear pink in colour and mint taste. Ora-sweet syrup vehicle is used as a flavouring vehicle for both oxycodone and placebo oral suspensions. IDS will determine the order of administration and delivers drug twice per day to be stored in a dedicated automated drug dispensing system for study participants. The pharmacy dispenses medications for each participant that corresponds with his/her allocated treatment group. Participants in the PR group receive four doses of oxycodone (5 mg) followed by one of four repeating schedules of administration alternating between oxycodone (5 mg) and placebo.

All participants will receive 0.4–1 mg of intravenous dilaudid or 1–4 mg dilaudid by mouth every 1 hour as needed for rescue and break through pain. Adjuncts (eg, lidocaine patches and other medication) can be given as rescue therapy. The rescue therapy will be managed by the acute pain management service (APMS) and the team will appropriately document use of dilaudid rescue therapy and any additional administered medication. APMS will monitor participants for safety during hospitalisation (phase I). When participants are pending discharge, APMS will contact IDS for the study allocation to prescribe the adequate treatment. Based on pain severity interference, emotional distress and drug assignment during hospitalisation (phase I), participants who did not receive opioids as part of the research study randomisation will be discharged with NSAIDs avoiding the prescription of opioids. Participants will be instructed to take the prescribed therapies such as baclofen, cyclobenzaprine, lidocaine patches, NSAIDs, acetaminophen, gabapentin or pregabalin. Based on the severity of the trauma, a prescription of oxycodone 5 mg every 4 hours, oxycodone 5 mg every 6 hours or Oxycodone 5 mg every 6 hours may be given for no more than 3–5 days and participants will be instructed to limit the opioids intake to strictly necessary circumstances. This is in accordance with current clinical practice at STC.

Thus, there are two instances in which the study team will become unblinded to treatment allocation: if a participant is being withdrawn from the study because they required more than three doses of rescue medication in a row, or at the end of phase I when APMS will recommend appropriate treatment for pain management. Otherwise, randomisation and treatment allocation will only be revealed to the study team once recruitment and data collection are complete.

The hospitalisation period will be inclusive of study enrolment to participant discharge as shown in table 1.

Participants are given an option to provide a blood sample while hospitalised and at the 6-month follow-up. Blood samples will be stored for future studies that will assess the correlation between circulating gene expression patterns and psychological and physiological phenotypes.

Participants will be asked to complete a series of questionnaires within 20–90 min after each study drug administration. Although the wording of the validated pain questionnaires we will use during hospitalisation cannot be changed, we will aim to frame questions about pain intensity and interference with function in such a way as to avoid nocebo effects (ie, asking how well they are able to perform their daily activities, how well they are able to interact with visitors/family and how well they are sleeping instead of how much pain are they experiencing). The completion of a psychological battery and questionnaires unrelated to pain are optional.

The following Patient-Reported Outcomes Measurement Information System (PROMIS) short-form scales will be administered each day of hospitalisation30:

Post-discharge, participants will be monitored for subsequent use of opioids at each of the four study follow-up visits: 2 weeks, 1 month, 3 months and 6 months. If the participant has consented to optional blood samples, the participant will return for additional bloodwork during each follow-up visit. The research team will communicate with participants via calls, letters, emails or texts to inquire about their health and medication use. A HIPAA-compliant app-based platform (eg, MetricWire) will be used to continue administration of all questionnaires remotely and facilitate communication between participants and the study team during the follow-up period.

The primary outcomes will be measured each day of hospitalisation including participant’s pain intensity and improvement (12 self-reported measurements via questionnaires and scales; see Clinical Assessment section for pain-related questionnaires), the rate of opioid intake (frequency and dosage), the quantity and rate of opioid rescue intervention requests and the quantity of opioid rescue interventions declined. Opioid intakes and rescue interventions will be documented in Epic and the case report form (CRF) by clinicians and trained research coordinators.

Secondary outcomes will be used to measure the proportion of enrolled trauma participants relative to the number accrued and screened. This measurement will determine the feasibility and inform appropriate power for a larger randomised controlled trial in the future.

Exploratory outcomes will be measured during the follow-up visits within 6-month post-discharge: use of opioids including long-term prescriptions, psychological questionnaires and pain scales (see Clinical Assessment section).

We conducted a survey of 50 participants suffering from chronic pain and a focus group in trauma inpatients to explore the possibility to conduct this dose-extending placebo-based trial. We have closely worked with the acute pain management team at STC to discuss feasibility and acceptability. Over several months of regular meetings and discussions to the original protocol, we worked diligently to ensure that the research question and outcome measures would be relevant to patients’ priorities, experiences and preferences. Based on this feedback and preliminary work, modifications to the original protocol have been done to limit barriers and challenges.

This study will enrol a total of 159 participants with 53 participants assigned to each of the three arms. We predict in the FD group that patients will take a maximum of 90 mg (5 mg every 4 hours for 3 days) and in PR group that patients will take a maximum dose of 45 mg (5 mg every 4 hours for the first 24 hours and then estimated every 6 hours for 2 days) with an overall reduction of opioids in the hospitalisation window of approximately 50%. We expect a small change in pain report (0.25%), and account for 20% participant withdrawal. Therefore, we will need to recruit 159 participants, with 53 participants per group, to achieve a significant difference across groups (alpha set at 0.05 and F equal to 3.054).

To test H1 and H2, linear mixed model (LMM) that accounts for unbalanced and missing data31 will be used to test differences in the primary and secondary outcomes among the three groups controlling for sex, age, race as well as severity of baseline pain and duration of hospitalisation. The LMM will allow us to account for missing data. Data will be analysed using the Statistical Package for Social Sciences (SPSS) v.24 software.

All source data collected via CRFs by research team members will be secured in the principal investigator’s (PI) locked file cabinets located in the locked clinical studies suite at the School of Nursing, Floor 7. All electronic data will be kept on a password protected University of Maryland Baltimore (UMB) computer. All data files will be password protected and only accessible to the research team to ensure confidentiality.

Some or all data may be stored on web-based electronic databases, which are secure, HIPAA compliant software systems managed by the School of Medicine at the University of Maryland, Baltimore. The project files linked to this project on the databases will only be shared with study personal and most research study personal users will only have access to de-identified data. The Virtual Private Network (VPN) for the databases will ensure security of project data collected. We will maintain integrity via programme set-up such as valid values and data rules. The programme will also detect any missing data or errors to improve the quality of data.

This study is reviewed annually by the PI and monitoring board. An interim analysis will be conducted when 25 participants have been randomised to each arm. Progress reports include reporting of adverse events, enrolment numbers, medical charts/clinical summaries, raw data, outcomes and preliminary analyses. The safety monitoring results will be reported to IRB.